This invention relates to diagnostic nuclear magnetic resonance ("NMR") imaging.
Magnetic resonance imaging ("MRI") has become an important tool in biomedical research and non-invasive medical diagnosis. It was first introduced by Lauterbur in 1973 and has developed considerably in the last decade to the point now that it is widely used for clinical imaging of humans in addition to being a powerful research tool.
The image contrast mechanisms of MRI are different from X-ray imaging and provide substantial contrast between certain soft tissues that are nearly identical using conventional radiological techniques. In MRI, the imaged spin is conventionally that of the proton. Most of the signal intensity comes from the most abundant proton in tissues, the water protons. MRI contrast (between image and background, and between images of adjacent tissues) usually relies on differences in the proton density, the transverse relaxation time (the time for recovery of the magnetization from a non-equilibrium state to its equilibrium value in the transverse x-y plane, also known as "T.sub.2 "), and the longitudinal relaxation time (the time for recovery of the magnetization from the non-equilibrium state to its equilibrium value in the external magnetic field's direction, also known as "T.sub.1 ").
While some soft tissues provide substantial contrast using MRI techniques, others yield a relatively low level of contrast. This has prompted the development of suitable MRI contrast-enhancing agents. Thus, the utility of NMR imaging in diagnostic medicine has been improved by the development of contrast agents which change the relaxation times of water protons in the vicinity of the agent. When the NMR contrast agent is sufficiently proximal to the component of body tissue under study, the agent decreases the relaxation times T.sub.1 and/or T.sub.2 of water protons in the vicinity of the tissue. Another way this is often expressed is to say that the agent increases the relaxivity, that is, it increases the relaxation rate (time and rate being inversely proportional). In this way, the NMR signal from the tissue of interest is enhanced relative to the background and to the surrounding tissues.
It would also be desirable to have an agent which would mediate changes in T.sub.1 or T.sub.2 in response to an electric field associated with physiological activity (or to a change in such a field), such as the membrane potential (or changes in membrane potential) associated with e.g. cellular membranes or neurons. Such an agent would permit MRI to be applied to the non-invasive study and diagnosis of bodily processes which involve such potentials. An agent having such capability has not heretofore been known, however.
The present invention relates more specifically to diagnostic agents containing a magnetic metal component, which agents are useful in magnetic resonance imaging. The agents of the present invention are useful in enhancing the contrast in conventional MRI. In addition, the agents of the present invention are useful in providing and enhancing contrast between potential states of a tissue which emanates, or which is capable of emanating, an electromagnetic field. For instance, as described more fully below, the agents would be responsive to cellular membrane potentials and changes in membrane potential.